What is a PASS study?

A PASS study (post-authorisation safety study) is:
a study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard or confirming the safety profile of the medicinal product. It can also be conducted with the aim of measuring the effectiveness of risk management measures.

a study in which the medicinal product is used in compliance with the conditions of the marketing authorisation. A PASS study may be an clinical trial (interventional) or a non-interventional study.

A PASS study may be initiated by the marketing authorisation holder voluntarily, or pursuant to a condition in the marketing authorisation, and it may be conducted in one or more European countries.

Must PASS studies be registered in the EU?

Yes, PASS studies must be registered in the electronic register for post-authorisation studies known as the EU PAS Register. The study protocol must be submitted to the register before the start of data collection. The Danish Health and Medicines Authority is not to be informed of PASS studies before they have been registered in the EU PAS Register.

When are PASS studies to be authorised by the Danish Health and Medicines Authority?

This depends on whether the PASS study is initiated voluntarily by the marketing authorisation holder or pursuant to a condition in the marketing authorisation granted by the Danish Health and Medicines Authority or a condition in a European marketing authorisation.

Non-interventional PASS studies which are initiated due to a condition in the marketing authorisation granted by the Danish Health and Medicines Authority must be authorised by the Danish Health and Medicines Authority if the study is only to take place in Denmark.

Non-interventional PASS studies which are initiated based on a condition in a European marketing authorisation are assessed, authorised and monitored by PRAC (the Pharmacovigilance Risk Assessment Committee) – a committee under the European Medicines Agency (EMA). The Danish Health and Medicines Authority does not authorise these studies. For more information, please see PRAC

Non-interventional PASS studies which are initiated voluntarily by the marketing authorisation holder must not be approved by the Danish Health and Medicines Authority.

Interventional PASS studies must be approved by the Danish Health and Medicines Authority.

When must I notify the Danish Health and Medicines Authority about non-interventional PASS studies?

The Danish Health and Medicines Authority must be notified of and receive documentation for non-interventional PASS studies when:

non-interventional PASS studies are initiated based on a condition in a marketing authorisation granted by the Danish Health and Medicines Authority.

non-interventional PASS studies are initiated based on a condition in a European marketing authorisation if the study takes place in Denmark. Documentation must be submitted after PRAC (Pharmacovigilance Risk Assessment Committee) has authorised the trial.

non-interventional PASS studies are initiated voluntarily by the marketing authorisation holder, if Denmark acts as reference member state or rapporteur for the medicinal product.

What is a Type A trial

A trial must satisfy the criteria below in order for it to be a Type A trial:

The investigational medicinal products to be tested are authorised in an EU or EEA country

The investigational medicinal products are tested in the patient population they are licensed for

The investigational medicinal products are tested under the licensed indication, dose and route of administration

The risk involved for the trial participants is on the same level as the risk of standard treatment

We offer an assessment time of 14 working days for Type A trials provided that the application is complete when we receive it. Further information is available here.

What is a tool trial?

A trial is a so-called tool trial when:

The sole objective of the trial is to study the physiological mechanisms of the body, and in which the medicinal product is used as a tool to induce a physiological response.

The trial does not have an actual pharmaceutical purpose, e.g. of uncovering/verifying a therapeutic, diagnostic or preventive effect and safety.

No data is gathered concerning the medicine's pharmacological effects, including pharmacodynamics and/or pharmacokinetics. Tool trials are not to be notified to the Danish Health and Medicines Authority. Further information is available here.

Must I report tool trials to the Danish Health and Medicines Authority?

No, this type of trial is not subject to a notification duty.

Can I get the Danish Health and Medicines Authority's assessment of whether a specific trial is to be approved?

If you are still not sure if the clinical trial in question should be notified to the Danish Health and Medicines Authority, you can send us an enquiry about the obligation to apply.

Such an enquiry must include the trial protocol and data about the product you wish to study. If the protocol is not yet completed, we can assess it based on a synopsis describing purpose, effect aims and a description of how these are to be achieved. Please send your enquiry to kf@dkma.dk.

How to submit the application to the Danish Health and Medicines Authority

Clinical trial applications can be submitted to the Danish Health and Medicines Authority via DKMAnet, on CD-ROM or via Eudralink.

Application via DKMAnet
Companies, including CROs (Contract Research Organisations) engaged in clinical trials of medicines in humans can apply for authorisation of clinical trials and submit notifications about ongoing trials to DKMAnet, our access-controlled extranet: Read more about Applying for clinical trial authorisations via DKMAnet.

Application on CD-ROM or via Eudralink
Applicants who do not have access to the DKMAnet can submit their documentation digitally on a CD-ROM or via Eudralink. Eudralink is the European Medicines Agency's (EMA's) system for secure file transfer.

It is accepted in certain cases to include subjects having a sterilised permanent partner or subjects using double barrier contraceptive methods. However, this should be explicitly justified in special circumstances arising from the study design, product characteristics and/or patient population. For the purpose of this guideline, double barrier methods of contraception means a condom combined with a diaphragm and spermicide.

The power of attorney for representatives from foreign authorities who are to monitor the trial, what must it give access to and for how long?

A power of attorney is only required if inspections are to be carried out by representatives from foreign authorities that will be monitoring the trial

By signing a power of attorney, trial subjects grant access to their entire patient record for a specific number of years.

If data from the trial is expected to be used for authorisation of a medicinal product, the number of years in which access is granted to the patient's record must take into account the time expected to pass until authorisation.

Please note the following minimum requirements for the power of attorney:

It must be clearly evident from a headline or a subheading that it is a power of attorney.

The wording "I hereby authorise..." must be used. Phrases such as "I give my consent to..." or "I am informed that..." are thus not accepted.

The power of attorney must apply to the entire patient record. Access to the patient record must thus not be limited to parts or relevant sections of the record.

The purpose of the power of attorney must appear (inspection/monitoring).

It must appear that access to the patient record applies during and after the trial in a period of up to at least 5 years after the end of the trial. Both a period and a number of years must be specified.

We recommend that no reference is made to any legislation since the power of attorney is based on contract law.

Authorisation to transfer data to third countries is not to be placed in the the power of attorney as it belongs under the Danish Data Protection Agency's legislation. The information on such transfer of data can instead be inserted in the information for trial subjects..

The power of attorney may be part of the consent form, but we recommend keeping consent form and power of attorney as two separate documents.

Please also be aware that it must appear from the information for trial subjects that the Danish Health and Medicines Authority and the sponsor have access to the entire patient record for monitoring and inspection purposes.

Is a comparator an investigational medicinal product?

What distinguishes background treatment from an investigational medicinal product?

Background treatment is not considered an investigational medicinal product when the following criteria are met:

The aim of the trial is not to gather information about the background treatment or the combination of background treatment and other investigational medicinal products in the protocol

The protocol does not make any specific requirements for the background treatment, apart from the requirement that it must be administered to all trial subjects in combination with the investigational medicinal product including the comparator

The protocol defines the background treatment without requiring that a specific trademark is used

The background treatment is the standard treatment in Denmark, and it is the treatment that would be offered to the trial subjects if they chose not to participate in the trial.

How often must I submit a report incl. a list of serious adverse reactions to the Danish Health and Medicines Authority?

Once a year throughout the trial period, you must submit a list of all serious suspected adverse reactions and a report on trial subject safety.

What is VHP?

The Voluntary Harmonisation Procedure (VHP) is a procedure which makes it possible to obtain coordinated assessment of an application for a clinical trial that is to take place in several European countries.

Which documents are to be submitted under a national VHP?

No later than three weeks after a clinical trial application has been approved via VHP, the application must be submitted to the participating national regulatory authorities for authorisation. The regulatory authorities must authorise the clinical trial within 10 days, provided the application is complete.

The application is to comprise the same elements as if it were an ordinary clinical trial application, cf. Appendix 10 of our guidelines. It is important to submit the same documentation which was authorised via VHP with the national application.

In addition to the documents submitted under VHP, the national application must include submission of the following documents:

An email from which it appears that the application has been approved under VHP

National EudraCT application form (PDF and XML file)

Form with invoice details

Label examples

Documentation proving that the manufacturer is notified of the trial

Patient information and power of attorney

What is a SUSAR?

A SUSAR is a Suspected Unexpected Serious Adverse Reaction. SUSARs must be reported to the Danish Health and Medicines Authority immediately.

An adverse reaction is a SUSAR if the reaction:

is serious, i.e. results in death, is life-threatening, requires hospitalisation or prolongation of hospitalisation,

results in persistent or significant disability or incapacity, or

causes congenital anomaly or birth defect.

The adverse reaction must be related to the investigational medicinal product. In other words, it is suspected that there is a causal relationship between use of the medicinal product and the adverse reaction that has occurred. Both investigator and sponsor must assess the causality. The sponsor must not override the investigator's evaluation, and reports where the sponsor does not agree with the investigator must be reported.

The adverse reaction must be unexpected, i.e. it must be an adverse reaction whose character or gravity is not consistent with the product information described in, for example, the Investigator's Brochure for an unlicensed investigational medicinal product or the summary of product characteristics for a licensed medicine.

If it is a blinded trial, the adverse reaction must be assessed before unblinding, but the data must be unblinded before they are reported to the Danish Health and Medicines Authority.

How should I submit SUSARs to the Danish Health and Medicines Authority?

The Danish Health and Medicines Authority forwards all reported SUSARs to EudraVigilance, so that they are included in the complete European adverse reaction data for the product concerned.

Which documentation must I submit, when I import medicines from countries outside the EU?

Please see the form "Documentation for good manufacturing practice (GMP) and the quality of investigational products in connection with the application for the conduct of clinical trials in Denmark" as well as the form "Qualified Person declaration". Please see section 7.1 of our guideline.

How is my trial registered in the EU Clinical Trials Register?

The EU Clinical Trials Register is compliant with the requirements of the International Committee of Medical Journal Editors (ICMJE), which provides that clinical trials must be registered prospectively in a public clinical trial register before the editors will accept articles on the trials for publication.

The EU Clinical Trials Register retrieves data from the EudraCT application form which is submitted to the Danish Health and Medicines Authority when a clinical trial is to be authorised. When we have registered that authorisation has both been given by the Danish Health and Medicines Authority and the Scientific Ethical Committee System in the database, data on the trial will be published.

How frequently is the sponsor expected to submit safety information to the investigator for clinical trials of medicinal products in humans?

Pursuant to the 'Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human use' (‘CT-3’), the sponsor must ensure that all relevant information regarding SUSARs is reported to the competent authorities and ethics committees as soon as possible and within seven days as regards fatal and life-threatening SUSARs and within 15 days for other SUSARs. The sponsor must also inform all investigators.

The purpose of informing the investigators is, according to CT-3, to inform the investigators about safety issues in light of reported SUSARs. The information must be concise and practical and where possible should be aggregated in a line listing of SUSARs in periods as warranted by the nature of the protocol/project and the volume of SUSARs generated. This line listing should be accompanied by a concise summary of the evolving safety profile of the product.

Furthermore, item 5.16.2 of the ICH GCP guideline provides that the sponsor should promptly notify all concerned investigators of findings that could adversely affect the safety of subjects or impact the conduct of the trial.

As a result of the above, the Danish Health and Medicines Authority does not stipulate a maximum number of days/weeks/months within which the investigators are to be informed of specific safety information. Generally, it would be inappropriate to establish a deadline for dealing with information regardless of nature, because the degree of importance will vary from case to case.

Consequently, some information will need to be sent to the investigator immediately, other information could wait and be sent out as regular line listings in periods decided by the sponsor for the individual project/protocol. This should be decided on a case-by-case basis.

What is required of the sponsor in relation to providing safety information to the investigator sites in the period from the Investigator's Brochure (IB) is final and until the trial is initiated at a site?

We will expect to find relevant safety information in the investigator's Trial Master File. Typically, this will be the latest Investigator's Brochure with subsequent SUSARs which have not yet been included in an Investigator's Brochure.

The information must reach the investigator well before the trial agreement is made and must be updated on a regular basis as required by the significance of the information.